We have advanced the theory that a major portion of enzymatic catalysis is achieved by activation of the substrate during binding. To support the theory, we have synthesized a large variety of test-tube models which simulate the bound substrate by being frozen in a single, favorable conformation and by having the interacting functions brought into the closest possible juxtaposition (stereopopulation control). These compounds undergo intramolecular reactions at rates comparable to those catalyzed by enzymes, sometimes even too fast to measure. It has been possible to generate high energy bonds within these models without energy input, simply using the free energy of formation of water and conformational restriction as the driving forces. In current work, models from sulfhydryl enzymes, oxidative phosphorylation and ion pumps are being developed. Techniques are being developed to elucidate molecular conformation in solution, based on 13C and 19F nmr spectroscopy, as well as computer calculations of conformational energies (CAMSEQ).